All instructor resources are now available on our Instructor Hub. The student resources previously accessed via GarlandScience. What are VitalSource eBooks? For Instructors Request Inspection Copy. Fundamentals of Environmental and Toxicological Chemistry: Sustainable Science, Fourth Edition covers university-level environmental chemistry, with toxicological chemistry integrated throughout the book.
Green Toxicology: a strategy for sustainable chemical and material development
This new edition of a bestseller provides an updated text with an increased emphasis on sustainability and green chemistry. The first chapter defines environmental chemistry and each of the five environmental spheres. The second chapter presents the basics of toxicological chemistry and its relationship to environmental chemistry.
Chapters then describe the atmosphere, its structure and importance for protecting life on Earth, air pollutants, and the sustainability of atmospheric quality. The author explains the nature of the geosphere and discusses soil for growing food as well as geosphere sustainability. He also describes the biosphere and its sustainability.
Green Toxicology: a strategy for sustainable chemical and material development
The final sphere described is the anthrosphere. The text explains human influence on the environment, including climate, pollution in and by the anthrosphere, and means of sustaining this sphere. Chapter 6 Biofuels and Bioenergy: An Overview of Biofuels and their Resources, 6. Chapter 7 Environmental Health and Energy Production: Read more Read less. Countdown to Christmas Sale. Sale ends on 24 December at Product description Product Description As its title implies, Energy: Kindle Edition File Size: Amazon Australia Services, Inc. Share your thoughts with other customers.
Therefore, the early assessment of toxicity before the first application to man clinical phase 1 plays a pivotal role in this process. Compounds for which the preclinical toxicological assessment identifies an adverse effect profile that exceeds the expected benefit for the patient will be excluded from progression in the development pipeline. Preclinical toxicology is hereby facing two challenges: This early assessment causes a shift from in vivo to in vitro to in silico methods.
Some toxicological effects can in the meantime be predicted based on in silico methods with reasonable reliability, such as mutagenicity, phospholipidosis, and to a lesser extent skin sensitization [ 86 ]. It can be foreseen that integrated testing strategies will evolve with the advent of AOPs and a better understanding of the mechanisms of toxicological effects, which comprise a combination of in silico and in vitro tools to predict toxicological effects.
For example, models that predict pharmacokinetic behaviour absorption, distribution of compounds based on physicochemical properties could be combined with predictions of liver transport based on QSAR transporter models. The inclusion of subsequent results from in vitro toxicity assays with hepatocytes or mitochondria will help to identify compounds that have a propensity towards drug-induced liver toxicity DILI. Such complementary tools may limit and remove the most problematic candidates in early phases or allow medicinal chemistry departments to optimize the structure early on.
Triggered by numerous publications on occurrence of pharmaceuticals in the environment, the European Commission was asked to deliver a strategic approach to pollution of water by pharmaceutical substances. The corresponding report was published in [ 87 ]. Despite these straightforward claims, the advances in the field of Green Toxicology for environmental safety are less evident than for human safety. The reason for this deficit is an inherent conflict of objectives during the optimization phase of a drug candidate, which is often overlooked in the discussion. One key criterion for low human toxicity is the partial stability of a drug candidate both with regard to human metabolism, as well as chemical stability towards light and temperature.
Unless we consider a so-called pro-drug, which requires metabolic activation for achieving efficacy, an otherwise unstable compound usually undergoes attrition during the drug development.
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Degradation or rapid metabolism of a drug candidate usually results in a lower exposure to the efficacious compound leading to a lower efficacy of disease treatment. This lower efficacy could only be overcome by increasing the dose, which in turn could result in an increased risk of side effects.
In addition, particular phase I metabolites or breakdown products may elicit adverse effects on their own, which can lower the therapeutic window. Striving for optimization of drug stability may result in the persistence of the drug after excretion and in sewage treatment in the aquatic environment. For some drugs, the concentrations reported in certain aquatic environments raise the concern of causing harm to environmental species.
As a matter of fact, the vast majority of active pharmaceutical ingredients show no ready biodegradability when subjected to the pertinent OECD screening tests for ready biodegradability [ 88 ]. Furthermore, there are currently no reliable tools or assays for predicting biodegradability in the early phases of drug development, which hinders the appropriate and desirable selection of biodegradable compounds.
Two case examples are presented below to illustrate the described difficulties in the inclusion of Green Toxicology for environmental safety assessment. Iodinated X-ray contrast media are used to enhance the contrast between organs or vessels and surrounding tissues during radiography. After renal excretion, iodinated X-ray contrast media contribute to the burden of adsorbable organic halogens AOX in sewage water [ 89 ].
The high doses required to achieve radiocontrast can only be administered intravenously if the compounds are both stable and of extremely low toxicity. In an effort to find alternative chemical core structures capable of carrying the radio-dense iodine, while at the same time being better biodegradable in the aquatic environment, iodine sugars were investigated as candidates for X-ray contrast media Fig. However, the attachment of only one iodine atom per sugar molecule was not sufficient to achieve the required radiocontrast at a feasible dose.
Therefore, alternative sugar dimers carrying two iodine atoms were investigated, but these showed a significant decrease in the degradability. In addition, the toxicity of the iodine sugar dimer proved to be 8. Furthermore, the sugar dimer showed low heat stability i. Due to these significant drawbacks, the chances of success in the search for alternative structures were considered to be inherently low, and the programme was subsequently stopped.
Degradation of iodinated sugar molecules. In both cases, these curves approximate the combination of the individual degradation curves of NaAc and the test compound, indicating that the test compound does not inhibit the degradation of NaAc by microcidal action.
The two oxazaphosphorines, ifosfamide and cyclophosphamide, belong to the most frequently used antineoplastic agents in cancer therapy. Due to their mutagenic and carcinogenic potential, concern was raised that the compounds might occur in the environment after excretion and cause harm to aquatic species.
Both compounds showed only minor biodegradability in laboratory-scale sewage treatment plants [ 91 ]. The intention of this modification is primarily to utilize the overexpression of glucose transporters GLUT in tumour cells for increased cellular uptake of the cytotoxic agents into cancer cells [ 93 ], thereby augmenting the efficacy of this alkylating drug candidate. Glufosfamide showed a significantly higher biodegradability compared with ifosfamide or cyclophosphamide; however, the criterion for ready biodegradability according to the OECD guidelines was also not achieved.
Structures of the marketed alkylating agent ifosfamide a and its glucose derivative, glufosfamide b. Unfortunately, and despite encouraging preclinical results pointing towards lower toxicity of glufosfamide compared with ifosfamide, several clinical trials have not resulted in the approval of the potential drug.
However, orphan drug status was granted for glufosfamide for pancreatic cancer by both the U.
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Clinical Trials [ 96 ] list nine studies with glufosfamide between April and Sept for a broad variety of cancers. A review by Calvaresia and Hergenrother [ 97 ] discusses the high dose-limiting human toxicity towards erythrocytes compared with the approved drug ifosfamide, with the main cause for the lack of clinical success of this compound stated as: Evidently, the glucose modification of the cytotoxic agents increase human toxicity rather than increase the efficacy of the drug, which contrasts with published preclinical results [ 97 ].
Thus, it is doubtful whether sugar attachment can be considered as a general design feature for degradable drugs due to the toxicity liabilities that such a chemical modification might introduce. Concluding the two presented case studies, there are currently no straightforward strategies available for the inclusion of Green Ecotoxicology into the early phases of drug development. Over the last two decades, nanomaterials are more and more in the focus of scientists, production companies, but also of regulators. This family of relatively new compounds and materials is different from the normal definition of chemical compounds.
Chemical substances are usually described by their chemical composition but in the case of nanomaterials, additional descriptors such as particle size, shape or composition of core and coatings are needed to specify and distinguish them from each other. As a consequence, a virtually unlimited number of different nanomaterials can be identified, which may result in a burdensome request for a large amount of toxicological data for regulatory hazard assessment. It is important to ensure that the development of new nanotechnology occur in the presence of Green Toxicology and Chemistry practices e.
A framework for chemists and material developers is needed to clearly outline design rules that integrate health, safety, and environmental concerns into nanotechnology development [ 98 ]. Thus, for Nanotechnology as a relatively young technology, the opportunity exists to start early on with the implementation of the principles of Green Toxicology. However, as highlighted by Hansen et al. Two examples of common nanotechnology are presented below that emphasize the complexity of early warning identification and integration of Green Toxicology practices.
Cosmetics, especially sunscreens, should protect us from ultraviolet UV -light induced sunburn and skin cancer. This protection has been achieved by a multitude of chemicals with different structures, some of which are under suspicion of being endocrine disruptors or of having other effects in environmental organism in receiving aquatic environments. Over the last two decades, nanoparticles consisting of ZnO or TiO 2 have been used as very efficient physical UV-blocking materials.
However, recently an intense discussion was started on the possible carcinogenic effect in the lung after inhalation of sun screens, as the International Agency for Research on Cancer IARC stated: This example brings together considerations about a product that has been on the market for decades, despite outcomes of experiments describing relatively severe effects in cells or animals. The idea of Green Toxicology may help to resolve this problem by introducing specific information about the materials used and by establishing relationships between the properties of the TiO 2 -particles and the predicted outcomes.
Comparisons of the materials used for the critical animal studies with that produced for the sunscreens should allow for the determination of the similarities in the materials and if the benign-by-design principle should be considered more thoroughly for future development of sunscreens. Another critical nanomaterial is carbon nanotubes CNTs , a lightweight but very strong material with a multitude of different possible applications in its various modifications i.
This material is described to have a strong similarity to asbestos with respect to the adverse health effects caused via inhalation. The properties of CNTs, such as the biopersistent, long fibre-like structure, and induction of oxidative stress, lead to the same biological consequences in lung tissue as asbestos, and thus, the use of CNTs is still under debate regarding the carcinogenic effect. Hence, this case study is an example of a situation where toxicological information for the production of benign CNTs already exists and should be used for future development of products.
As mentioned above, more and more products that consist of or contain nanomaterials will soon enter the market or are already in use. An adequate risk assessment of environment and health is seemingly not possible because of the tremendous need for biological experiments, animal testing and laboratory capacity. The usefulness and applicability of in vitro methods must be demonstrated on a case-by-case basis, but they represent enabling technologies to address these demands [ , ].
There are also opportunities for in silico approaches and pragmatic solutions such as grouping and thresholds of toxicological concern. Thus, the concepts of read-across and grouping, which are described in detail for chemicals by the OECD and ECHA, should also be introduced for nanomaterials. As mentioned earlier, the starting position for this approach is the formation of groups of chemicals or materials which have the same properties for a specific aspect.
Thus, a grouping of nanomaterials combined with a corresponding evaluation and test strategy based on, for example, their physicochemical properties or toxicological characteristics, would reduce regulatory testing efforts. This has already been recognized early on and several grouping frameworks have been proposed [ — ]. The concept of Walser et al. The chemical composition of each structural element core, coating, etc. These biunique entities may include many similar nanomaterial identities, which are considered the same from a regulatory perspective.
In a second step, entities are allocated to groups clouds , which represents specific testing strategies for toxicological endpoints that need further evaluation [ ]. This allocation is driven by AOPs [ 27 ], in which key events are triggered in a cascade-like manner, ultimately leading to an undesirable biological response [ , ]. In addition to hazard-oriented key events, properties such as stability or bioaccumulation can serve as further building blocks for testing strategies [ ].
Bio-persistent accumulative entities of nanomaterials, capable of inducing key events responsible for long-term toxicity, would be allocated to a testing strategy where further testing is needed. In contrast, nanomaterials that are not triggering such key events would be allocated to a group where no such additional testing is required.
The assignment of substances and nanomaterials to predefined testing strategies based on AOPs further support Green Toxicology. Data on the induction of key events of relevant AOPs could be screened by in vitro assays and serve as gatekeepers in innovation processes. The cases shown above for chemical and pharmaceutical companies, as well as nanotechnology development, clearly demonstrate that Green Chemistry, together with the principles of Green Toxicology more specifically related to the environmental and health effects of compounds or materials, may achieve a sustainable and safe production scenario of new chemicals.
However, in the case of pharmaceutical compounds, there may also be limitations with regard to achieving safe and efficacious drugs that are at the same time environmentally friendly. As the examples from the European Environmental Agency EEA demonstrate [ 16 ], it is now the duty of all the stakeholders to implement such rules for a responsible production of new compounds and materials based on common principles. Taking the ideas of Maertens et al. It is not only important to test early, but to also try to achieve safety-by-design of the compounds, to use predictive test systems, and to avoid exposure.
Overall, testing itself must be sustainable and safe by avoiding solvents that may be hazardous or energy consuming, and testing should help to reduce the need of experimental animals. Moreover, the ideas and fundamental rules of toxicology should be familiar for all chemists but also to physicists and engineers. Thus, a transdisciplinary education in toxicology would be helpful to implement this knowledge in the processes for chemical development Fig. Last but not least, such measures are not free of charge, hence, all stakeholders should be convinced to use these principles and the consumer has to accept the higher costs for such products.
As a very important step in producing chemicals and materials for future applications regarding environmental- and health-safety issues, the goals of Green Toxicology have to be accepted by all societal groups. SC wrote the first draft of the manuscript.
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Bennard van Ravenzwaay, Email: National Center for Biotechnology Information , U. Published online Apr 4. Gallen, Switzerland Find articles by Harald F.
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Author information Article notes Copyright and License information Disclaimer. Received Jan 5; Accepted Mar This article has been cited by other articles in PMC. Associated Data Data Availability Statement The datasets supporting the conclusions of this article are included within the article. Abstract Green Toxicology refers to the application of predictive toxicology in the sustainable development and production of new less harmful materials and chemicals, subsequently reducing waste and exposure.
Background Over the past two decades, the movement of Green Chemistry has become a new standard embraced for the development of less harmful materials and chemicals that are safer for both the environment and consumers [ 1 , 2 ]. Open in a separate window. Integration of Green Toxicology in discovery, development and production practices In order to efficiently develop new compounds or products with the desired technological or biological traits and lesser toxicity, many different structures need to be evaluated.
Predictive toxicology using in silico tools In silico toxicology relies on the use of computational methods to analyse, model, and predict the toxicity of chemicals, which complement traditional and innovative toxicity tests for risk and hazard assessments. Predictive toxicology using omics and in vitro tools In the initial stages of chemical development, the identification of the sequential processes and perturbations of biological pathways at a molecular level e.
Precautionary principle Additional lessons for Green Toxicology can be learned from past product development and production through the application of the precautionary principle [ 17 , 18 ]. Green Toxicology and animal testing: Skin and eye irritation studies The traditional in vivo Draize irritation test for skin and eyes, in which a restrained, conscious animal is exposed dermal and ocular, respectively to a test substance for a set amount of time to determine toxicological effects, has long since been criticized for the limitations in species differences, subjective scoring, and experimental variability.
Skin sensitization studies Skin sensitization is a process more complex than skin or eye irritation, and includes several key events such as 1 dermal penetration, 2 protein reactivity, 3 inducing stress responses in keratinocytes, 4 activation of immune cells dendritic cells in the skin, and 5 their translocation to the lymph nodes.
Acute toxicity testing The endpoint of systemic toxicity has not been of major interest to chemical companies and regulatory bodies. Endocrine disruption To screen for compounds with endocrine effects, two in vitro systems are often used that address the most common causes for endocrine activity: Neurotoxicity Another important aspect of systemic toxicity, with respect to avoidance of chemicals, with a problematic hazard profile is neurotoxicity.
Developmental toxicity The last, and possibly the most important endpoint in toxicology, which has been investigated in screening strategies, is the toxic effects on development.
Fundamentals of Environmental and Toxicological Chemistry: Sustainable Science, Fourth Edition
New tools With new omics technologies becoming more readily available, we are now at a point where there is a chance to tackle complex toxicological concerns, such as systemic toxicity. Green Toxicology in drug development for human safety assessment In contrast to household and consumer chemicals, where the optimization process of the properties during product development is often independent of the safety assessment, the drug development process can be seen as a series of iterative steps to optimize efficacy and simultaneously lower the safety as early as possible.
Green Toxicology for the early assessment of environmental safety Triggered by numerous publications on occurrence of pharmaceuticals in the environment, the European Commission was asked to deliver a strategic approach to pollution of water by pharmaceutical substances. Green Toxicology for nanomaterials: Nanomaterials—endless variability needs new tools for assessment As mentioned above, more and more products that consist of or contain nanomaterials will soon enter the market or are already in use.
Conclusions The cases shown above for chemical and pharmaceutical companies, as well as nanotechnology development, clearly demonstrate that Green Chemistry, together with the principles of Green Toxicology more specifically related to the environmental and health effects of compounds or materials, may achieve a sustainable and safe production scenario of new chemicals.